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Cortical thickness mediates the relationship between DRD2 C957T polymorphism and executive function across the adult lifespan

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Abstract

Dopamine (DA) signaling is critical for optimal cognitive performance. Aging is accompanied by a change in the strength of this signaling, with a loss of striatal and extrastriatal D2 binding potential. The reduction in dopamine modulation with age negatively influences various aspects of cognition. DRD2 C957T (rs6277) impacts DA D2 receptor density and availability, with C homozygotes linked to lower striatal DA availability and reduced executive functioning (EF), but also high extrastriatal binding potential. Here, we investigated in 176 participants aged 20–94 years whether: (1) DRD2 C carriers differ from T carriers in cortical thickness or subcortical volume in areas of high concentrations of D2 receptors that receive projections from mesocortical or nigrostriatal dopaminergic pathways; (2) whether the DRD2*COMT relationship has any synergistic effects on cortical thickness; (3) whether the effect of DRD2 on brain structure depends upon age; and (4) whether DRD2-related regional thinning affects executive function performance. We show that DRD2 impacts cortical thickness in the superior parietal lobule, precuneus, and anterior cingulate (marginal after FDR correction), while statistically controlling sex, age, and COMT genotype. Specifically, C homozygotes demonstrated thinner cortices than both heterozygotes and/or T homozygotes in an age-invariant manner. Additionally, DRD2 predicted executive function performance via cortical thickness. The results highlight that genetic influences on dopamine availability impact cognitive performance via the contribution of brain structure in cortical regions influenced by DRD2.

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Data availability

Data are available upon request from the corresponding author and analyses used standard publicly available software pipelines.

Notes

  1. Creating the thickness construct without the marginally significant anterior cingulate region did not alter the mediation model effects.

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Acknowledgements

This study was supported in part by the National Institutes of Health (Grants AG-036848, AG-036818, AG-056535) and AWARE foundation and BvB Dallas grants. The authors thank Marci Horn, Asha Unni, and Elizabeth Reese for their assistance with neuropsychological testing, and Elizabeth Reese for her help with FreeSurfer processing and manual edits.

Funding

This study was supported in part by the National Institutes of Health (Grants AG-036848, AG-036818, AG-056535) and AWARE foundation and BvB Dallas grants.

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Correspondence to Kristen M. Kennedy.

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Miranda, G.G., Rodrigue, K.M. & Kennedy, K.M. Cortical thickness mediates the relationship between DRD2 C957T polymorphism and executive function across the adult lifespan. Brain Struct Funct 226, 121–136 (2021). https://doi.org/10.1007/s00429-020-02169-5

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  • DOI: https://doi.org/10.1007/s00429-020-02169-5

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